Camptothecin (CPT), originally isolated from the Chinese tree Camptotheca acuminate, possesses potent antitumor properties that emerge from its inhibition of topoisomerase I (Hsiang et al., Camptothecin Induces Protein-Linked DNA Breaks Via Mammalian DNA Topoisomerase-I. J Biol Chem 1985, 260, 4873; Lavergne et al., Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res 1999, 59, 2939; Saltz et al., The camptothecins. Lancet 2003, 361, 2235). However, CPT exhibits several properties that severely limit its clinical application such as low aqueous solubility, (Lerchen et al., Design and optimization of 20-O-linked camptothecin glycoconjugates as anticancer agents. J Med Chem 2001, 44, 4186; Klein et al., Synthesis and in vivo antitumor activity of poly(L-glutamic acid) conjugates of 20(S)-camptothecin. J Med Chem 2003, 46, 190; Saltz et al., id.) high levels of protein binding, and rapid inactivation through lactone ring hydrolysis. The insolubility of CPT has severely restricted its clinical application and has led to the development of several water soluble congeners, which are in various phases of clinical trials or in the clinic (Potmesil, Camptothecins—from Bench Research to Hospital Wards. Cancer Res 1994, 54, 1431). Camptothecin undergoes a reversible, pH-dependent ring opening reaction between the active lactone (closed E-ring) and inactive carboxylate (open E-ring) form, which has also been shown to be toxic (Greenwald et al., 20-O-acylcamptothecin derivatives: Evidence for lactone stabilization. J Org Chem 2000, 65, 4601; Lerchen et al., id). Lactone hydrolysis is also enhanced by the specific binding and sequestration of the carboxylate form to various proteins, such as human serum albumin, in the biological matrix, which shifts the equilibrium further toward the carboxylate form. Thus, the clinical utility of CPT has been severely hindered by the hydrolytic instability of its E-lactone ring in blood serum (Jaxel et al., Structure-Activity Study of the Actions of Camptothecin Derivatives on Mammalian Topoisomerase-I-Evidence for a Specific Receptor-Site and a Relation to Antitumor-Activity. Cancer Res 1989, 49, 1465; Hertzberg et al., Modification of the Hydroxy Lactone Ring of Camptothecin—Inhibition of Mammalian Topoisomerase-I and Biological-Activity. J Med Chem 1989, 32, 715; Fassberg et al., A Kinetic and Mechanistic Study of the Hydrolysis of Camptothecin and Some Analogs. J Pharm Sci 1992, 81, 676; Burke et al., The Structural Basis of Camptothecin Interactions with Human Serum-Albumin—Impact on Drug Stability. J Med Chem 1994, 37, 40). Additionally, considerable variability in the oral and intravenous bioavailability of CPT suggests poor cellular and tumor uptake of unmodified CPT drugs (Sinka et al., Tumor-targeted bioconjugate based delivery of camptothecin: design, synthesis and in vitro evaluation. J Control Release 2004, 100, 275).
